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Goals: 1) Understand the mechanism for ↑LDL in Type II diabetes 2) Having previously established the link between endothelial cell damage (loss of inhibitory.

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Presentation on theme: "Goals: 1) Understand the mechanism for ↑LDL in Type II diabetes 2) Having previously established the link between endothelial cell damage (loss of inhibitory."— Presentation transcript:

1 Goals: 1) Understand the mechanism for ↑LDL in Type II diabetes 2) Having previously established the link between endothelial cell damage (loss of inhibitory GAG) and abnormal smooth muscle migration & proliferation, Integrate ↑LDL into scheme of atherosclerosis - accumulation of LDL cholesterol in the macrophage to form “foam cells” Final Exam: Explain abnormal accumulations of smooth muscle and lipid in atherosclerosclerosis of Type II diabetics

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3 Approach: -normal regulation of lipid metabolism by insulin (↑ TG in adipose tissue) - theoretical abnormalities in lipid metabolism with insulin resistance - “insulin-resistant syndrome”: why ↑TG, ↑LDL & obesity ?? - hyperglycemia & AMP Kinase - selective insulin resistance -lipid-centric approach -obesity represents the epigenetic cause of insulin resistance in susceptible individuals

4 Dysregulation of lipid metabolism in the “Metabolic Syndrome” If insulin resistant- why are some obese?

5 Insulin resistance of Type II diabetes - reduced receptor concentration with hyperinsulinemia - reduced signaling due to abnormal phosphorylation of insulin receptor substrate 1 - increased FFA with “metabolic syndrome” impairs insulin sensitive glucose transport

6 Insulin targets: - ↑ endothelial cell LPL → ↑ plasma FFA -↑ hepatic & adipose TG synthesis from FFA (prevents FFA entry into mitochondria for oxidation by increasing malonyl CoA) -↓ lipolysis in adipose tissue by inhibition of hormone sensitive lipase - ↑ LDL endocytosis From Medical Physiology, (eds Boron & Boulpaep) page 999

7 Insulin & lipid metabolism: clear plasma of TG & store energy as fat - prevents FFA oxidation by ↑ malonyl CoA & preventing FFA entry into mitochondria for oxidation** - facilitates hepatic TG synthesis (TG appear in plasma as VLDL) - stimulates lipoprotein sensitive lipase on endothelium to release FFA from TG - inhibits lipolysis via inhibition of hormone-sensitive lipase ___________________________________________________________________________________________ Insulin resistance & dyslipidemia in the Metabolic Syndrome ↑ TG & ↑ small density LDL ↓ HDL **If insulin resistant, why ↑plasma TG, LDL & obesity? Should mobilize fat stores & oxidize fat.

8 If insulin resistant, why obese? -elevated insulin to normalize glucose -Insulin inhibition of lipolysis is most Insulin-sensitive parameter

9 “Metabolic Syndrome” If insulin resistant, should oxidize FFA, & in adipose tissue, have less lipogenesis & greater lipolysis (maybe not greater lipolysis) If insulin resistant, why obese with ↑plasma TG &LDL? -hyperglycemia (acting through AMP kinase & increased substrate→ ↑ malonyl CoA → ↑ TG) -Insulin resistance may not exist in liver (↑ malonyl CoA → ↑ TG & LDL) Additional components with metabolic syndrome: -sedentary lifestyle - ↓ exercise; through AMP kinase, ↑ malonyl CoA - “emotional stress” - ↑ cortisol → ↑appetite & ↑insulin resistance → ↑ glucose - aging & obesity - ↓ exercise - ↓ activity of hormone sensitive lipase (mobilize less “central” fat) - leptin resistance - ↑ appetite - obesity/depression - ↑ appetite

10 Obesity as the epi-genetic cause of insulin resistance in genetically susceptible individuals Obesity: 1) Decreased sensitivity of glucose-induced insulin secretion - can manifest as hyperinsulinemia with normal blood glucose (J Clin Inves 81:442,1988) lipo-centric approach Obesity → decreased insulin receptor concentration Decreased insulin-sensitive glucose uptake → hyper-insulinemia to normalize blood glucose Hyper-insulinemia with “normal” insulin sensitivity on inhibition of lipolysis → abnormally greater inhibition of lipolysis Hyper-insulinemia with “normal” insulin sensitivity in liver → greater inhibition of lipid oxidation, greater ↑TG & LDL

11 Insulin resistance “most, if not all, of the other tissues of the body retain normal insulin sensitivity in the face of muscle and adipose tissue insulin resistance” (Endo Metab Clin N Am 34:49,2005) Hence: with increased insulin (response to hyperglycemia secondary to insulin resistance in sk mus & fat), exagerated inhibition of hepatic FFA oxidation and enhanced TG synthesis

12 Final Exam Preparation: Compose a cohesive explanation for the pathophysiology & pharmacological prophylaxis of atherosclerosis in the insulin-resistant (metabolic) syndrome. Suggestions: - lipocentric approach (obesity → decreased insulin-sensitive glucose uptake → hyper-insulinemia) - increased plasma concentration of LDL (ex: possible hyperglycemia effects on AMP kinase & normal insulin sensitivity in liver → reduced lipid oxidation, ↑ TG & LDL) - significance of elevated LDL (ex: induces endothelial binding of monocytes, which infiltrate sub-endothelial space, differentiate into macrophages, incorporate LDL and present as “foam cell”) -endothelial damage & loss of inhibitory ECM GAG leading to abnormal SMC proliferation (ex: summarize evidence discussed regarding loss of inhibitory heparan sulfate GAG)

13 Attached references: AMP Kinase Foam Cell Formation

14 1)Intestinal chylomicrons (85% triglycerides & 3% cholesterol )→lymph→plasma - lipoprotein lipase* on vascular endothelium releases FFA from TG on chylomicrons - FFA transported into skeletal muscle and adipose tissue* 2)Liver processes remnant chylomicrons (TG depleted & cholesterol rich) & exports VLDL (triglyceride rich ) to plasma - hepatic FFA oxidation inhibited* & TG synthesized - lipoprotein lipase* on vascular endothelium releases FFA from TG on VLDL* 3) FFA diffuse into adipose tissue → ↑TG - lipolysis inhibited* 4) Plasma triglyceride depleted VLDL = LDL (cholesterol rich) 5) Small/dense LDL formed (exchange of some LDL cholesterol with TG of VLDL; subsequent hydrolysis of TG generates dense LDL) 6) LDL (cholesterol rich) enter cells by receptor-mediated endocytosis* 7) HDL accumulate cholesterol from LDL & cell membranes; liver extracts & excretes cholesterol from HDL * Insulin sensitive. Normal flow of chylomicrons → VLDL → LDL → HDL


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